PROJECT SUMMARY White adipose tissue (WAT) is a critical organ in whole body glucose and lipid homeostasis. In obesity and type 2 diabetes (DM2), WAT function is compromised, resulting in lipid deposition in ectopic tissues such as liver and muscle, impaired glucose and lipid homeostasis, and a chronic low grade inflammatory state. De novo lipogenesis (DNL) has recently emerged as a key aspect of WAT function. Studies performed during the first funding cycle of this award have contributed to that notion by demonstrating that (1) DNL in WAT is low in obesity, diabetes and cachexia and seems to be a marker of metabolic health in both rodents and humans; (2) leptin and insulin control WAT DNL via brain leptin and insulin signaling; and (3) environmental triggers that induce the metabolic syndrome such as overeating and binge drinking impair the ability of brain insulin signaling to regulate WAT functionality. Our preliminary data suggest that a neuronal circuit originating from AgRP neurons in the medio-basal hypothalamus regulates WAT DNL and inflammation and systemic substrate utilization. Interestingly, after high fat feeding (HFD) as a model for human obesity and metabolic syndrome, AgRP activation still drives food intake, but fails to govern WAT DNL and inflammation, or substrate utilization. In a model of cachexia, AgRP activation fails to regulate WAT DNL and inflammation, substrate utilization and food intake. In aim one of the current proposal we aim to map the sympathetic outflow pathways originating from AgRP neurons that connect synaptically to WAT and to functionally characterize specific projections of AgRP neurons in these different metabolic and consummatory functions of AgRP neurons. In aim two we plan to examine the role of brain insulin, glucose and leptin in regulating the efferent pathways originating from AgRP neurons. In aim three we plan to test if the sympathetic nervous system is the key relay mechanism through which the CNS regulates WAT DNL using innovative approaches to study the specific roles of catecholaminergic signaling, parasympathetic and sympathetic innervation. Understanding how adipose tissue functionality can be restored in obesity and diabetes may point towards therapeutic strategies that ameliorate or prevent metabolic disorders.